Advertisement

BioMetals

, Volume 24, Issue 1, pp 171–180 | Cite as

Cardioprotective effect of zinc requires ErbB2 and Akt during hypoxia/reoxygenation

  • Kasi Viswanath
  • Sreedhar Bodiga
  • Victor Balogun
  • Anita Zhang
  • Vijaya Lakshmi BodigaEmail author
Article

Abstract

Recent literature suggests that exogenous zinc can prevent ischemia reperfusion injury by activating phosphoinositide-3 kinase (PI3K)/Akt and by targeting the mitochondrial permeability transition pore (mPTP). It is known that ErbB2 expression promotes association and activation of PI3-kinase/Akt, resulting in growth and survival of cardiac myocytes. In this study, we found that zinc-induced ErbB2 protein expression and Akt activation are required for preventing reperfusion injury. Neonatal rat cardiac myocytes subjected to 8 h of hypoxia, followed by 16 h of reoxygenation induced cardiomyocyte apoptosis, as assessed by increased caspase-3 activity, annexin V staining and lowered MTT reduction and ATP levels. However, addition of zinc-pyrithione (ZPT) before onset of reoxygenation effectively lowered the apoptotic indices and restored the ATP levels. ZPT induced a significant increase in ErbB2 protein expression and Akt activation. Pretreatment with Hsp 90 inhibitor, geldanamycin or PI3-kinase inhibitor, wortmannin prevented the increase in ATP levels and abrogated the protective effect of zinc-pyrithione. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the ErbB2 protein expression and Akt activation.

Keywords

Zinc Cardiomyocytes Hypoxia Reoxygenation ErbB2 Akt Hsp90 

References

  1. Apostolova MD, Ivanova IA, Cherian MG (1999) Metallothionein and apoptosis during differentiation of myoblasts to myotubes: protection against free radical toxicity. Toxicol Appl Pharmacol 159:175–184CrossRefPubMedGoogle Scholar
  2. Baliga RR, Pimental DR, Zhao YY, Simmons WW, Marchionni MA, Sawyer DB, Kelly RA (1999) NRG-1-induced cardiomyocyte hypertrophy. Role of PI-3-kinase, p70(S6K), and MEK-MAPK-RSK. Am J Physiol 277:H2026–H2037PubMedGoogle Scholar
  3. Bancila V, Nikonenko I, Dunant Y, Bloc A (2004) Zinc inhibits glutamate release via activation of pre-synaptic KATP channels and reduces ischaemic damage in rat hippocampus. J Neurochem 90:1243–1250CrossRefPubMedGoogle Scholar
  4. Beyersmann D, Hasse H (2001) Functions of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals 14:331–341CrossRefPubMedGoogle Scholar
  5. Bialik S, Cryns VL, Drincic A, Miyata S, Wollowick AL, Srinivasan A, Kitsis RN (1999) The mitochondrial apoptotic pathway is activated by serum and glucose deprivation in cardiac myocytes. Circ Res 85:403–414PubMedGoogle Scholar
  6. Bodiga S, Zhang R, Jacobs DE, Larsen BT, Tampo A, Manthati VL, Kwok WM, Zeldin DC, Falck JR, Gutterman DD, Jacobs ER, Medhora MM (2009) Protective actions of epoxyeicosatrienoic acid: dual targeting of cardiovascular PI3K and KATP channels. J Mol Cell Cardiol 46:978–988CrossRefPubMedGoogle Scholar
  7. Buja LM, Eigenbrodt ML, Eigenbrodt EH (1993) Apoptosis and necrosis. Basic types and mechanisms of cell death. Arch Pathol Lab Med 117:1208–1214PubMedGoogle Scholar
  8. Chanoit G, Lee S, Xi J, Zhu M, McIntosh RA, Mueller RA, Norfleet EA, Xu Z (2008) Exogenous zinc protects cardiac cells from reperfusion injury by targeting mitochondrial permeability transition pore through inactivation of glycogen synthase kinase-3beta. Am J Physiol Heart Circ Physiol 295:H1227–H1233CrossRefPubMedGoogle Scholar
  9. Chanoit G, Lee S, Xu Z (2009) Reply to “letter to the editor: ‘zinc and cardioprotection: the missing link’ ”. Am J Physiol 296:H235Google Scholar
  10. Chavany C, Mimnaugh E, Miller P, Bitton R, Nguyen P, Trepel J, Whitesell L, Schnur R, Moyer J, Neckers L (1996) p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2. J Biol Chem 271:4974–4977CrossRefPubMedGoogle Scholar
  11. Coudray C, Charlon V, de Leiris J, Favier A (1993) Effect of zinc deficiency on lipid peroxidation status and infarct size in rat hearts. Int J Cardiol 41:109–113CrossRefPubMedGoogle Scholar
  12. Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, Peterson KL, Chen J, Kahn R, Condorelli G, Ross J Jr, Chien KR, Lee KF (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8:459–465CrossRefPubMedGoogle Scholar
  13. Fuller SJ, Sivarajah K, Sugden PH (2008) ErbB receptors, their ligands, and the consequences of their activation and inhibition in the myocardium. J Mol Cell Cardiol 44:831–854CrossRefPubMedGoogle Scholar
  14. Galasso SL, Dyck RH (2007) The role of zinc in cerebral ischemia. Mol Med 13:380–387CrossRefPubMedGoogle Scholar
  15. Giannakis C, Forbes IJ, Zalewski PD (1991) Ca2+/Mg2+-dependent nuclease: tissue distribution, relationship to inter-nucleosomal DNA fragmentation and inhibition by Zn2+. Biochem Biophys Res Commun 181:915–920CrossRefPubMedGoogle Scholar
  16. Gordon LI, Burke MA, Singh AT, Prachand S, Lieberman ED, Sun L, Naik TJ, Prasad SV, Ardehali H (2009) Blockade of the erbB2 receptor induces cardiomyocyte death through mitochondrial and reactive oxygen species-dependent pathways. J Biol Chem 284:2080–2087CrossRefPubMedGoogle Scholar
  17. Grazette LP, Boecker W, Matsui T, Semigran M, Force TL, Hajjar RJ, Rosenzweig A (2004) Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol 44:2231–2238CrossRefPubMedGoogle Scholar
  18. Griffin TM, Valdez TV, Mestril R (2004) Radicicol activates heat shock protein expression and cardioprotection in neonatal rat cardiomyocytes. Am J Physiol Heart Circ Physiol 287:H1081–H1088CrossRefPubMedGoogle Scholar
  19. Hellyer NJ, Kim MS, Koland JG (2001) Heregulin-dependent activation of phosphoinositide 3-kinase and Akt via the ErbB2/ErbB3 co-receptor. J Biol Chem 276:42153–42161CrossRefPubMedGoogle Scholar
  20. Jacob C, Maret W, Vallee BL (1998) Control of zinc transfer between thionein, metallothionein, and zinc proteins. Proc Natl Acad Sci USA 95:3489–3494CrossRefPubMedGoogle Scholar
  21. Kang YJ, Li G, Saari T (1999) Metallothionein inhibits ischemia-reperfusion injury in mouse heart. Am J Physiol 276:H993–H997PubMedGoogle Scholar
  22. Karagulova G, Yue Y, Moreyra A, Boutjdir M, Korichneva I (2007) Protective role of intracellular zinc in myocardial ischemia/reperfusion is associated with preservation of protein kinase C isoforms. J Pharmacol Exp Ther 321:517–525CrossRefPubMedGoogle Scholar
  23. Krezel A, Hao Q, Maret W (2007) The zinc/thiolate redox biochemistry of metallothionein and the control of zinc ion fluctuations in cell signaling. Arch Biochem Biophys 463:188–200CrossRefPubMedGoogle Scholar
  24. Kupatt C, Dessy C, Hinkel R, Raake P, Daneau G, Bouzin C, Boekstegers P, Feron O (2004) Heat shock protein 90 transfection reduces ischemia-reperfusion-induced myocardial dysfunction via reciprocal endothelial NO synthase serine 1177 phosphorylation and threonine 495 dephosphorylation. Arterioscler Thromb Vasc Biol 24:1435–1441CrossRefPubMedGoogle Scholar
  25. Lal A (1991) Effect of zinc sulphate on infarct size in experimental myocardial infarction in dogs. Indian J Med Res 94:316–319PubMedGoogle Scholar
  26. Lee S, Chanoit G, McIntosh R, Zvara DA, Xu Z (2009) Molecular mechanism underlying Akt activation in zinc-induced cardioprotection. Am J Physiol Heart Circ Physiol 297:H569–H575CrossRefPubMedGoogle Scholar
  27. Malhotra R, Brosius FC III (1999) Glucose uptake and glycolysis reduce hypoxia-induced apoptosis in cultured neonatal rat cardiac myocytes. J Biol Chem 274:12567–12575CrossRefPubMedGoogle Scholar
  28. Maret W (1995) Metallothionein/disulfide interactions, oxidative stress, and the mobilization of cellular zinc. Neurochem Int 27:111–117CrossRefPubMedGoogle Scholar
  29. Mizukami Y, Iwamatsu A, Aki T, Kimura M, Nakamura K, Nao T, Okusa T, Matsuzaki M, Yoshida K, Kobayashi S (2004) ERK1/2 regulates intracellular ATP levels through alpha-enolase expression in cardiomyocytes exposed to ischemic hypoxia and reoxygenation. J Biol Chem 279:50120–50131CrossRefPubMedGoogle Scholar
  30. Mocanu MM, Yellon DM (2009) Letter to the editor: “zinc and cardioprotection: the missing link”. Am J Physiol 296:H233–H234Google Scholar
  31. Muthuswamy SK, Gilman M, Brugge JS (1999) Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol 19:6845–6857PubMedGoogle Scholar
  32. Neckers L (2002) Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 8:S55–S61CrossRefPubMedGoogle Scholar
  33. Nicotera P, Leist M, Ferrando-May E (1998) Intracellular ATP, a switch in the decision between apoptosis and necrosis. Toxicol Lett 102–103:139–142CrossRefPubMedGoogle Scholar
  34. Peng X, Guo X, Borkan SC, Bharti A, Kuramochi Y, Calderwood S, Sawyer DB (2005) Heat shock protein 90 stabilization of ErbB2 expression is disrupted by ATP depletion in myocytes. J Biol Chem 280:13148–13152CrossRefPubMedGoogle Scholar
  35. Plas DR, Talapatra S, Edinger AL, Rathmell JC, Thompson CB (2001) Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J Biol Chem 276:12041–12048CrossRefPubMedGoogle Scholar
  36. Powell SR, Aiuto L, Hall D, Tortolani AJ (1995) Zinc supplementation enhances the effectiveness of St. Thomas’ Hospital No. 2 cardioplegic solution in an in vitro model of hypothermic cardiac arrest. J Thorac Cardiovasc Surg 110:1642–1648CrossRefPubMedGoogle Scholar
  37. Pugatsch T, Abedat S, Lotan C, Beeri R (2006) Anti-erbB2 treatment induces cardiotoxicity by interfering with cell survival pathways. Breast Cancer Res 8:R35CrossRefPubMedGoogle Scholar
  38. Reed JC, Paternostro G (1999) Postmitochondrial regulation of apoptosis during heart failure. Proc Natl Acad Sci U A 96:7614–7616CrossRefGoogle Scholar
  39. Shiraishi J, Tatsumi T, Keira N, Akashi K, Mano A, Yamanaka S, Matoba S, Asayama J, Yaoi T, Fushiki S, Fliss H, Nakagawa M (2001) Important role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis. Am J Physiol Heart Circ Physiol 281:H1637–H1647PubMedGoogle Scholar
  40. Stanley WC, Chandler MP (2002) Energy metabolism in the normal and failing heart: potential for therapeutic interventions. Heart Fail Rev 7:115–130CrossRefPubMedGoogle Scholar
  41. Taimor G, Lorenz H, Hofstaetter B, Schluter KD, Piper HM (1999) Induction of necrosis but not apoptosis after anoxia and reoxygenation in isolated adult cardiomyocytes of rat. Cardiovasc Res 41:147–156CrossRefPubMedGoogle Scholar
  42. Thornalley PJ, Vasak M (1985) Possible role for metallothionein in protection against radiation-induced oxidative stress: Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim Biophys Acta 827:36–44CrossRefPubMedGoogle Scholar
  43. Vali L, Stefanovits-Banyai E, Szentmihalyi K, Drahos A, Sardy M, Febel H, Feher E, Bokori E, Kocsis I, Blazovics A (2008) Alterations in the content of metal elements and fatty acids in hepatic ischemia-reperfusion: induction of apoptotic and necrotic cell death. Dig Dis Sci 53:1325–1333CrossRefPubMedGoogle Scholar
  44. White RL, Wittenberg BA (2000) Mitochondrial NAD(P)H, ADP, oxidative phosphorylation, and contraction in isolated heart cells. Am J Physiol Heart Circ Physiol 279:H1849–H1857PubMedGoogle Scholar
  45. Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, Neckers L (2001) Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem 276:3702–3708CrossRefPubMedGoogle Scholar
  46. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137CrossRefPubMedGoogle Scholar
  47. Zaarur N, Gabai VL, Porco JA Jr, Calderwood S, Sherman MY (2006) Targeting heat shock response to sensitize cancer cells to proteasome and Hsp90 inhibitors. Cancer Res 66:1783–1791CrossRefPubMedGoogle Scholar
  48. Zeng J, Heuchel R, Scahffner W, Kagi JH (1991) Thionein (apometallothionein) can modulate DNA binding and transcription activation by zinc finger containing factor Sp1. FEBS Lett 279:310–312CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Kasi Viswanath
    • 1
  • Sreedhar Bodiga
    • 1
  • Victor Balogun
    • 2
  • Anita Zhang
    • 2
  • Vijaya Lakshmi Bodiga
    • 2
    Email author
  1. 1.Cardiovascular Center, Medical College of WisconsinMilwaukeeUSA
  2. 2.Blood Research InstituteMilwaukeeUSA

Personalised recommendations